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MOF: New therapies on the horizon Immunostimulating therapies

MOF: New therapies on the horizon Immunostimulating therapies. 31 st ISICEM Brussels March 22-25, 2011 Gold Room at the Congress Center in Brussels. 08.15-08.30 March 25 2011. George J. Baltopoulos Professor of Critical Care, Athens University School of Nursing

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MOF: New therapies on the horizon Immunostimulating therapies

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  1. MOF: New therapies on the horizonImmunostimulating therapies 31stISICEM Brussels March 22-25,2011 Gold Roomat the Congress Center in Brussels 08.15-08.30 March 25 2011 George J. Baltopoulos Professor of Critical Care, Athens University School of Nursing ICU at Agioi Anargyroi Hospital of Kifissia, Greece www.icutopics.gr or .com gbaltop@gmail.com

  2. Sepsis Trauma Burns Drugs Surgery Systemic temporary immunosupression mild severe Impairs antimicrobial defense Prevents inflammation induced damage High susceptibility to infections homeostasis

  3. Simplified description of systemic pro- and anti-inflammatory immune responses over time after septic shock: Time matters!! Pro-inflammatory Response The anti-inflammatory surge is termed the compensatory anti-inflammatory response syndrome (CARS) Anti-inflammatory interventions 24-48 hours Immunostimulation interventions /Pro-inflammatory drugs ? Time Early mortality ≈20% Anti-inflammatory Response In somepatients, CARS is pathologically exaggerated and prolonged (beyond 48 hours)→Immunoparalysis Late Mortality ≈80%

  4. Is /was the septic patient immunocompetent? • Yes, if the patient finally survives !! But • There is a period of marked immunosupression (1-7 days) necessary to brake down the initial pro-inflammatory response • most survivors of sepsis start spontaneously to recover immune functions 3-4 days post admission/septic episode • The magnitude and the duration of immunosupression matters !!

  5. How we quantitate the immunosupression? • IL-10 • The higher the level of IL-10 the lower the level of HLA-DR • HLA-DR • Reduced mHLA-DR expression has been proposed as a global biomarker of sepsis-associated immunosuppression. • Volk HD et al. Clin Transplant 1989;3:246–252 • Volk HD et al. Chem Immunol 2000;74:162–177 • TNF-α Production post ex vivo peripheral blood stimulation with LPS • The higher the level of HLA-DR the higher the level of ex vivo TNF-α production

  6. Immunosupression monitoring and outcomes- available evidence • 13/ 23 infected patients on ICU admission recovered the ex vivo TNF production and survived • Munoz C et al. J. Clin. Invest. 1991;88:1747-1754 • 42 pts with sepsis, decreasing serum levels of IL-10 indicates survival • van der Poll T et al. The Journal of Infectious Diseases 1997; 175:118-22 • 38 Septic shock pts. High IL-10 and low HLA-DR are associated with mortality • Monneret G et al. Immunology Letters 95 (2004) 193–198 • 93 Septic shock pts. Persisting low HLA-DR expression predicts mortality • Monneret G et al. Intensive Care Med 2006; 32:1175–1183 • 14 burn pts. HLA-DR persistent decrease was associated with mortality and the development of septic shock • Tissot S et al. Crit Care Med 2007; 35:1910–1917 • 37/105 trauma pts. Low HLA-DR was correlated with infection • CheronA et al. Critical Care 2010, 14:R208 • Low HLA-DR is independently associated with secondary nosocomial infections after septic shock. • Landelle C et al. Intensive Care Med 2010; 36:1859–1866 • 283 pts HLA-DR does not predict mortality. In 70 ICU pts > 7 days in ICU the recovery slope predicts the secondary infections after 7 days. • Lukaszewicz A-C et al. Crit Care Med 2009; 37:2746–2752

  7. What is the target of immune stimulation?? • (1) to help bacterial killing at the primary focus of infection • (2) to prevent the development of nosocomial infections • (3) to prevent the reactivation of dormant viruses

  8. HLA-DR in severely injured patients is markedly reduced can be increased significantly by IFN-γ Ex vivo HERSHMAN MJ, et al. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin. exp. Immunol. 1989; 77: 67-70

  9. Ex Vivo The horizontal line shows the mean values of untreated samplesof healthy controls with the two dotted lines indicating the standarddeviation Inflamm Res 2007; 56:38–44

  10. Conclusions: GM-CSF and IFN-γ may serve to support immune functions in severely injured patients. Ex Vivo Inflamm Res 2007; 56:38–44

  11. Cardiac arrest: The evolution of mHLA-DR expression in circulating monocytes pre & post interferon (100γ Sc) • The evolution of mHLA-DR expression in circulating monocytes before, during, and after treatment with interferon-γ and BAL culture after cardiac arrest. Lukaszewicz A-C, et al. Monocytic HLA-DR expression in intensive care patients: Interest for prognosis and secondary infection prediction. Crit Care Med 2009; 37:2746–2752

  12. Septic shock: The evolution of mHLA-DR expression in circulating monocytes pre & post interferon • The evolution of mHLA-DR expression in circulating monocytes before, during, and after treatment with interferon-γ after initial septic shock. Lukaszewicz A-C, et al. Monocytic HLA-DR expression in intensive care patients: Interest for prognosis and secondary infection prediction. Crit Care Med 2009; 37:2746–2752

  13. IFN-γ restored the deficient HLA-DR expression and ex vivo LPS-induced TNF- secretion post sepsis Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients Höflich C, Döcke W-D, Meisel C, Volk H-D. Regulatory immunodeficiency and monocyte deactivation Assessment based on HLA-DR expression Clinical and Applied Immunology Reviews 2 (2002) 337–344

  14. Interferon-γ (100 μg/m2sc) on the 2nd post postoperative day,increases monocyte HLA-DR expression • IFN-γ exerts a favorable effect on cell-mediatedimmunity in patients after major surgery without effects on glucoseand lipid metabolism. N=7 N=6 de Metz J, et al. Interferon-γ increases monocyte HLA-DR expression without effects on glucose and fat metabolism in postoperative patients. J Appl Physiol 96: 597–603, 2004

  15. Immunoparalysis and 100 μg Interferon-γ inhalation x 3/day x 7 days in Trauma 52 pts with severe trauma (ISS>16) HLA-DR of alveolar macrophages at days 2 or 3 Immunoparalysis was detected in 21 pts (40%) who were older and sicker. HLA-DR < 30 % (n = 21) ↑ PAF, phospholipase A2, IL-1β and AM HLA-DR ↓ IL-10 Placebo (n = 10) Infection II : 5 50 % Interferon-gamma (n = 11) Infection II : 1 9 % p < 0.05 Nakos G et al. Crit Care Med 2002;30:1488-1494

  16. GM-CSF Reversed Sepsis-associated Immunosuppression in 9 severe sepsis patients • HLA-DR < 150 mean fluorescence intensity (MFI) over a period of at least 48 h prior to intervention • 5 µg/kg per day rhGM-CSF over a period of 3 days • Mortality rate was 33% Ex vivo stimulation Nierhaus A, et al. Reversal of immunoparalysis by recombinant human GM-CSF in patients with severe sepsis. Intensive Care Med 2003; 29:646–651

  17. GM-CSF (72 hrs Inf-γ 125 μg/m2) in Septic Patients N=15 • Higher leukocyte count, increased mHLA-DR, and better resolution of infections • Increased HLA-DR expression was associated with clearance of infection (p=0.02) • No difference in mortality (14/14 vs. 9/15) • GM-CSF elevated HLA-DR in all treated patients to a level not different from healthy controls (p= 0.27) N=18 Monocyte HLA-DR was significantly lower than healthy control subjects on all patients (p < 0.01). Rosenbloom AJ, et al. Effect of granulocyte-monocyte colony-stimulating factor therapy on leukocyte function and clearance of serious infection in nonneutropenic patients. Chest 2005; 127: 2139–2150

  18. p < 0.12 GM-CSF: Ten severe sepsis and respiratory dysfunction patients vs. 8 controls BAL ns p<0.01 PBlood ns p<0.08 BAL ns p<0.02 Presneill JJ, et al. A Randomized Phase II Trial of GM-CSF Therapy in Severe Sepsis with Respiratory Dysfunction Am J Respir Crit Care Med 2002;166:138–143

  19. Blood Granulocytes H2O2 p ns 0.02 p< 0.05 ns GM-CSF: Ten severe sepsis and respiratory dysfunction patients vs 8 controls Alveolar cell phagocytic function p ns ns Blood granulocyte phagocytic function • GM-CSF : • was associated with improved gas exchange without pulmonary • neutrophil infiltration, despite circulating neutrophils functional activation • was not associated with worsened ARDS or the MODS, • homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction? Presneill JJ, et al. A Randomized Phase II Trial of GM-CSF Therapy in Severe Sepsis with Respiratory Dysfunction Am J Respir Crit Care Med 2002;166:138–143

  20. Prospective, randomized, placebo-controlled, double-blind clinical trial • Adults with severe sepsis/septic shock underwent immune monitoring. Those with monocyte HLA-DR expression < 8,000 molecules/cell for 2 days were randomized to get SQ GM-CSF or placebo for 8 days (Biomarker-guided GM-CSF therapy) • Monocyte HLA-DR expression, ex vivo LPS-induced TNF-α production, cytokines, and outcomes were measured

  21. n = 19 patients per limp

  22. Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence • There was no increase either in IL-6 or IL-10 systemic levels in the GM-CSF-treated group. • There were no GM-CSF-related adverse events reported. • Underpowered to address mortality. • Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay.

  23. 28-day mortality of G-CSF or GM-CSF therapy versus placebo Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

  24. In-hospital mortality of G-CSF or GM-CSF therapy versus placebo Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

  25. Reversal rate from infection of G-CSF or GM-CSF therapy versus placebo Bo L, et. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

  26. Adverse events of G-CSF or GM-CSF therapy versus placebo. Conclusions: There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

  27. Conclusion • Reduced HLA-DR (and /or the ex vivo LPS stimulation TNFα production) has been proposed as a global biomarker of immunosuppression • Any immunostimulating intervention should be relied on patient immune status evaluation • Consider immunostimulation within the first week post ICU admission/ sepsis • Most likely GM-CSF and IFN-γ are useful treatment modalities • Large prospective multicenter clinical trials investigating mHLA-DR-guided immunostimulating therapy in patients with sepsis are warranted to investigate clinical parameters and mortality as primary endpoints Thank you for your attention Ευχαριστώ για την προσοχή σας

  28. Greece is always wonderful

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